1. Field of the Invention
The present invention relates to preparation of microparticles. More particularly, the present invention relates to apparatus and methods for preparing microparticles using liquid extraction of solvent in the emulsion.
2. Related Art
Various methods are known that can encapsulate compounds in the form of microparticles. It is particularly advantageous to encapsulate a biologically active or pharmaceutically active agent within a biocompatible, biodegradable wall forming material (e.g., a polymer) to provide sustained or delayed release of drugs or other active agents. In emulsion-based methods, the material to be encapsulated (drugs or other active agents) is generally dissolved, dispersed, or emulsified in a solvent containing the wall forming material to form a discontinuous phase. The discontinuous phase is combined with a continuous phase to form an emulsion. Solvent is then removed from the emulsion droplets to form the hardened microparticle product.
One approach to solvent removal is to evaporate the solvent, such as by vacuum or heating. One drawback of solvent removal through evaporation is the length of time that is required to remove a sufficient quantity of solvent so that any remaining residual solvent is at an acceptably safe level for use of the microparticles by humans and other animals. The length of time for solvent removal through evaporation can be reduced somewhat by using aqueous extraction of solvent in conjunction with solvent evaporation. An example of such a combined evaporative and aqueous extraction process is described in U.S. Pat. No. 4,389,330. However, such a combined evaporative and aqueous extraction process is not suitable, much less optimal, for solvents that are not amenable to evaporation, such as benzyl alcohol.
Other conventional emulsion-based processes for preparing microparticles rely solely on aqueous extraction of solvent, such as the process described in U.S. Pat. No. 5,407,609. One drawback of aqueous extraction of solvent is the large volume of water that is required. As noted in U.S. Pat. No. 5,407,609, the volume of the extraction medium should be at least the volume needed to dissolve all of the solvent out of the emulsion droplets, such as a volume 10-fold or higher. This problem is particularly acute when the microparticles are being prepared on a commercial scale. Larger and/or more equipment is required to accommodate the large volume of water in the process, resulting in higher equipment and disposal costs.
Thus, there is a need in the art for an improved method and apparatus for preparing microparticles. There is a particular need in the art for an improved process of solvent removal that overcomes the drawbacks of conventional evaporative and aqueous extraction techniques. The present invention, the description of which is fully set forth below, solves the need in the art for such a method and apparatus.
In one aspect of the present invention, a method of preparing microparticles is provided that comprises the following steps: forming an emulsion, the emulsion comprising a first phase and a second phase, the first phase comprising a polymer, an active agent, and a solvent; separating a portion of the second phase from the emulsion to form a separated second phase; extracting from the separated second phase at least a portion of the solvent present in the separated second phase to form an extracted separated second phase; and returning the extracted separated second phase to the emulsion. The extracting and returning steps may be repeated until a selected level of solvent in the emulsion is reached. The separating step may be carried out by filtering, such as with a membrane filter, the portion of the second phase from the emulsion. The extracting step may be carried out by extracting the solvent into an extraction liquid, which may be miscible with the solvent and a non-solvent for the polymer, the active agent, and the second phase. The extracting step may be carried out in a contactor comprising a hollow fiber. After the returning step, the emulsion may be combined with a quench liquid, such as by transferring the emulsion to a vessel containing the quench liquid, and/or through the use of a static mixer.
In another aspect of the present invention, a method of preparing microparticles is provided that comprises the following steps: forming an emulsion, the emulsion comprising a first phase and a second phase, the first phase comprising a polymer, an active agent, and a solvent; separating a portion of the second phase from the emulsion to form a separated second phase; and replacing the separated second phase in the emulsion with a quantity of a solution. The separating step may be carried out by filtering, such as with a membrane filter, the portion of the second phase from the emulsion. The separating step may be carried out by filtering the second phase from the emulsion using a filter disposed in a diafiltration unit. The separating step may comprise pumping the separated second phase to remove it. The separating step and the replacing step may be performed simultaneously. The separating and replacing steps may be repeated until a selected level of solvent in the emulsion is reached.
In yet a further aspect of the present invention, a method of preparing microparticles is provided that comprises the following steps: forming an emulsion, the emulsion comprising a first phase and a second phase, the first phase comprising a polymer, an active agent, and a solvent; maintaining a separation between the emulsion and an extraction liquid; and extracting the solvent into the extraction liquid. The maintaining step may be carried out by providing a membrane between the emulsion and the extraction liquid. The maintaining step may comprise transferring the emulsion to a vessel fitted with a membrane, the membrane defining a channel disposed in the vessel. The extracting step may be carried out by allowing the solvent to diffuse from the emulsion across the membrane into the channel. The extracting step may be repeated until a selected level of solvent in the emulsion is reached.
In yet another aspect of the present invention, a system for preparing microparticles is provided. The system comprises a first vessel configured to contain an emulsion. The first vessel includes a filter that separates the first vessel into a first portion and a second portion. A contactor, comprising a hollow fiber, is in fluid communication with the first portion and with the second portion of the first vessel. A second vessel, configured to contain an extraction liquid, is in fluid communication with the contactor. A first pump is configured to pump the extraction liquid through the contactor to extract solvent from a continuous phase of the emulsion. A second pump is configured to pump the continuous phase through the contactor.
In still a further aspect of the present invention, a system for preparing microparticles is provided. The system comprises a vessel configured to contain an emulsion. A membrane is disposed in the vessel, the membrane defining a channel in the vessel. A pump is configured to pump an extraction liquid through the channel to extract solvent from a continuous phase of the emulsion.
A feature of the present invention is that solvent is extracted from the emulsion phase prior to quenching. The extraction is performed more slowly than conventional aqueous extraction processes that need to be performed quickly.
A feature of the present invention is that a portion of the continuous phase is separated from the emulsion, solvent is extracted from that portion, which is then returned to the emulsion. The extraction and return process is repeated until a selected level of solvent in the emulsion is reached.
It is a further feature of the present invention that it can be carried out using a non-aqueous extraction liquid, such as heptane or octamethylcyclotetrasiloxane (OMCTS).
Still a further feature of the present invention is that extraction of the solvent can be carried out using a hollow fiber contactor.
Yet a further feature of the present invention is that extraction of the solvent can be carried out in the vessel containing the emulsion by allowing the solvent to diffuse across a membrane fitted into the vessel.
An advantage of the present invention is that it reduces the volume of quench liquid, typically water for injection (WFI) that is required.
The present invention advantageously overcomes disposal problems found in conventional aqueous extraction processes. Firstly, the process of the present invention uses a reduced volume of liquid overall so there is less volume to be disposed. Secondly, a non-aqueous extraction liquid such as heptane can be disposed of cleanly and efficiently through burning. Thus, the cost of disposal is reduced.
Another advantage of the reduced volume of liquid in the process is that smaller scale equipment and less quench liquid can be used to produce a given batch size of microparticles than with a conventional aqueous extraction process. With smaller water requirements, larger batch sizes may be produced using the same equipment and WFI capacity.